Submissions for variant NM_000122.2(ERCC3):c.1115_1120dup (p.Trp374Ter)

gnomAD frequency: 0.00003  dbSNP: rs778865255

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001822132	SCV002064431	likely pathogenic	not provided	2020-08-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ERCC3 gene demonstrated a six-base pair duplication in exon 8, c.1115_1120dup. This sequence change results in a premature stop codon at amino acid position 374, p.Trp374*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ERCC3 protein with potentially abnormal function. This sequence change has not been previously described in patient with ERCC3-related disorders. Other truncating sequence changes, upstream and downstream to this position, have been reported in association with ERCC3-related disorders (PMIDs: 16947863). This sequence change has been described in the gnomAD database with a low population frequency of 0.003% (dbSNP rs778865255). Collectively, these evidences indicate that, this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001822132	SCV002133057	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp374*) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs778865255, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ERCC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1335950). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002489864	SCV002780301	likely pathogenic	Xeroderma pigmentosum group B; Trichothiodystrophy 2, photosensitive	2021-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001822132	SCV003805548	likely pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226493	SCV003922511	likely pathogenic	Xeroderma pigmentosum	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: ERCC3 c.1115_1120dupAGCAGT (p.Trp374X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations upstream, and downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 3.2e-05 in 251448 control chromosomes (gnomAD). The variant, c.1115_1120dupAGCAGT, has been reported in the literature in individuals affected with pediatric tumors (Byrjalsen_2020, Kim_2021). These reports do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.